Cancer Stem Cells and Tumor Microenvironment Group

Introduction


BIOGRAPHY
Dr. Bruno Sainz, a virologist by training, earned his PhD in Microbiology and Immunology from Tulane University in New Orleans, LA (USA) in 2005. His early scientific career focused on viral infections, such as Herpes simplex virus type-1, Ebola Virus, and SARS-CoV. Specifically, his research focused on developing inhibitors of viral entry and understanding and exploiting the innate immune Interferon (IFN) response to combat viral infections (funded by a National Institutes of Health (NIH, USA) NRSA research award). As a postdoctoral fellow at the Scripps Research Institute (2005-2006), he developed a more physiologically relevant hepatocyte culture system to study Hepatitis C Virus (HCV) infection in vitro. The more differentiated hepatocyte system also permitted him, while at the University of Illinois in Chicago (2006-2011), to independently discover that the Niemann-Pick C1-Like 1 (NPC1L1) cholesterol absorption receptor is an HCV entry factor and the clinically-available and FDA-approved NPC1L1 antagonist ezetimibe (Zetia) can potently block HCV uptake in vitro and in mice with human liver grafts. These findings translated into a 2012 Nature Medicine publication, a US patent, invited talks and presentations at international conferences and institutes and several follow-up publications. As a semi-independent investigator at the CNIO in Spain from 2011-2014, Dr. Sainz changed his research focus and began to study cancer stem cell (CSC) biology in pancreatic cancer. He identified several immune proteins that have powerful pro-CSC properties, including the human cationic antimicrobial protein 18 (hCAP-18)/LL-37 peptide and the Interferon-Stimulated Gene 15 protein (ISG15). The sum of these studies have advanced our understanding of CSC pathobiology. In addition to the contributions described above, his contributions to science and specifically to the CSC field are best exemplified by his numerous publications aimed at dissecting the biological and molecular signatures of CSCs. Over the past 6 years as an independent Ramón y Cajal investigator at the Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, his laboratory has discovered a new inherent biomarker present in CSCs, known autofluorescence, which is the result of riboflavin accumulation in ABCG2-coated intracellular vesicles exclusively found in CSCs. Using this marker, his laboratory has learned that CSCs are distinct from their non-CSCs counterparts at the epigenetic level (e.g. genome methylation and miRNA profiles) and these differences in methylation and miRNA expression are necessary for the maintenance of these cells. In addition, his laboratory has also learned that CSCs are metabolically different than non-CSCs. While non-CSCs meet their energy requirements via glycolysis, CSCs depend on mitochondrial respiration (i.e. oxidative phosphorylation) to survive. Thus, mitochondrial respiration represents an Achille’s heel of CSCs, and his group is exploiting new experimental compounds and targeting specific genes (e.g. ISG15) in order to alter CSC metabolic requirements. In summary, the accomplishments and research of the Sainz Lab have resulted in more than 65 publications, several awarded US (Cancer Research Institute, Concern Foundation), Spanish (ISCIII, AECC, ACANPAN, Beca FERO) and European (EURO-NanoMed) grants, 3 patent applications, numerous invited talks and presentations, editorial affiliations and international recognition. Dr. Sainz has a broad background in immunology, microbiology and oncology, with specific expertise in pancreatic cancer, small animal models of cancer and drug discovery.



RESEARCH INTERESTS
Cancer stem cells (CSCs), also known as tumor-initiating cells or tumor-propagating cells, constitute a biologically unique subset of stem-like cells within the bulk tumor cell population. These cells are believed to be important in metastasis and chemoresistance, and they are hypothesized to be key drivers of the multistep process of oncogenesis, giving rise to the clonogenic core of tumor tissues. In the Sainz laboratory, we study CSCs in the context of pancreatic ductal adenocarcinoma (PDAC), the 4th leading cause of cancer related deaths in developed countries. We are running a combined basic and translation research program, which synergistically combines studies on the biology of mouse and human CSCs, including their in vivo microenvironment, in order to enhance our understanding of the regulatory machinery of CSCs. Specifically, the avenues of research that the Sainz laboratory pursues, are:

1) The identification and characterization of new biomarkers for the detection of CSCs from different solid tumors. We have recently discovered a new inherent biomarker present in CSCs across several solid tumors. This biomarker, known as autofluorescence, is the result of riboflavin accumulation in ABCG2-coated intracellular vesicles exclusively found in CSCs. We are currently using autofluorescence as a means of isolating CSCs for in depth biological and molecular characterization studies.

2) The identification of proteins that govern key CSC phenotypes, such as “stemness", epithelial to mesenchymal transition (EMT), oxidative phosphorylation (i.e. mitochondrial respiration) and chemoresistance. We have discovered that the Interferon Stimulated Gene 15 (ISG15) is not only up-regulated in CSCs, but its function as a Ubiquitin-like modifier is necessary for many CSCs biological processes.

3) Comprehensively understand the cellular make-up of the CSC niche and the larger more complex tumor microenvironment, specifically the role of tumor-associated macrophages (TAMs) in "activating" CSCs, with respect to the different environmental proteins they can secrete in response to cues from the tumor and how these proteins alter the function of the CSCs at the level of EMT and chemoresistance.



RECENT PUBLICATIONS
The Sainz laboratory has recently published several important papers and reviews in the cancer stem cell and pancreatic cancer field:

1) Loss of ISG15 expression and ISGylation Reduces Mitophagy and the Functionality and Metabolic Plasticity of Pancreatic Cancer Stem Cells. Nature Communications. 2020. in press

2) Pancreatic cancer-derived organoids - a disease modeling tool to predict drug response. United European Gastroenterol J. 2020 Feb 19:2050640620905183. PMID32213029

3) The Anthrax Toxin Receptor 1 (ANTXR1) Is Enriched in Pancreatic Cancer Stem Cells Derived from Primary Tumor Cultures. Stem Cells Int. 2019 May 2;2019:1378639. PMID31191663

4) Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF. Cancer Cell. 2019 Apr 15;35(4):573-587.e6. PMID30975481

5) Tumor-associated macrophage-secreted 14-3-3ζ signals via AXL to promote pancreatic cancer chemoresistance. Oncogene. 2019 Jul;38(27):5469-5485. PMID30936462

6) Levels of autophagy related 5 protein affect progression and metastasis of pancreatic tumors in mice. Gastroenterology. 2019 Jan;156(1):203-217.e20. PMID30296435

7) Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nature Medicine. 2018 Jul 24(7):954-960. PMID29808009

8) Current perspectives on the crosstalk between lung cancer stem cells and cancer-associated fibroblasts. Crit Rev Oncol Hematol. 2018 May;125:102-110. PMID29650269

9) The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer. Cancers. 2018 Jan 26;10(2). pii: E33. PMID29373514

10) Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci USA (PNAS). 2018 Feb 6;115(6):E1147-E1156. PMID29351990

11) A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet. Clin Transl Med. 2017 Dec;6(1):3. PMID28050779

12) GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut. 2017 Sep;66(9):1665-1676. PMID27325420

13) Current evidence for cancer stem cells in gastrointestinal tumors and future research perspectives. Crit Rev Oncol Hematol. 2016 Nov;107:54-71. PMID27823652

14) DNMT1 inhibition reprograms pancreatic cancer cells via upregulation of the miR-17-92cluster. Cancer Research. 2016 Aug 1;76(15):4546-58. PMID27261509

15) The ever-changing landscape of pancreatic cancer stem cells. Pancreatology. 2016 Apr 14. pii: S1424-3903(16)30018-7. PMID27161173

16) Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies. Mediators of Inflammation. 2016:9012369. PMID26980947

17) MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells. Cell Metabolism. 2015 Oct 6;22(4):590-605. PMID26365176

18) The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 2015 Dec;64(12):1936-48. PMID25887381

19) Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut. 2015 Dec;64(12):1921-35. PMID25841238

20) ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Research. 2014 Dec 15;74(24):7309-20. PMID25368022

21) Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nature Methods. 2014 Nov;11(11):1161-9. PMID25262208

FULL LIST OF PUBLICATIONS



FUNDING
Our laboratory is currently funded by several national and international grants, including:

1) Project Title: “RuCSC” - targeting cancer stem cells using ruthenium compounds
Funding Source: Programa Ignicia prueba de concepto, an initiative of the Agencia Gallega de Innovación (GAIN) to facilitate the access of I+D+i projects to the market. This project, financed with 386.603 Euros is a collaborative project between la Universidad de Santiago de Compostela (USC) and la Universidad Autónoma de Madrid (UAM). More Information

2) Project Title: Combating Pancreatic Cancer by Identifying Those Genes Essential for Cancer Stem Cell-Mediated Tumorigenicity
Funding Source: Fundación Fero - 2018 BECA FERO FELLOWSHIP

3) Project Title: Photoactivable nanoparticles to immunostimulate the tumour microenvironment in pancreatic cancer (PANIPAC)
Funding Source: EURONANOMED III - JOINT TRANSNATIONAL CALL FOR PROPOSALS (2018)

4) Project Title: Proyecto FIS (PI18/00757) - The basal subtype of pancreatic cancer as a new tool towards personalized medicine: cellular and molecular characterization for the development of new therapies
Funding Source: ISCII & Spanish Ministry of Science, Innovation & Universities

5) Project Title: Identification of pancreatic cancer immune escape receptors.
Funding Source: Asociación Cáncer de Páncreas (ACANPAN)

6) Project Title: A multi-faceted approach to treating pancreatic cancer.
Funding Source: Asociación Española Contra el Cáncer (AECC), Grupos Coordinados Estables 2016: CNIO (Dr. Mariano Barbacid), IRyCIS (Dr. Alfredo Carrato) and UAM (Dr. Bruno Sainz)

7) Project Title: Targeting ISG15, an Achilles' heel of cancer stem cells.
Funding Source: CONquer CanCER Now Award, Concern Foundation, LA, CA, USA

8) Project Title: Proyecto FIS (PI15/01507) - Development of a liquid biopsy assay to isolate circulating cancer stem cells in the blood for their characterization and validation as a biomarker for early detection of pancreatic cancer
Funding Source: ISCII & Spanish Ministry of Innovation & Competiveness (MINECO)

9) Project Title: Development of a state-of-the art liquid biopsy assay for the detection of circulating cancer stem cells fused to macrophages in human blood samples
Funding Source: Thermo Fisher Scientific, Attune® NxT Acoustic Flow

10) Project Title: Ramón y Cajal Merit Award
Funding Source: Spanish Ministry of Innovation & Competiveness (MINECO)



LINKS
We collaborate in several European initiatives and are part of the national Spanish network of health research centers:

ORCID

Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

PDAC-AECC


Sainz Anding, Bruno
Investigador Contratado



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